At the recent 2012 symposium of the Multinational As sociation of Supportive Care in Cancer (MASCC), held in New York City, experts discussed a wide range of topics related to management of treatmentinduced side effects. Below are some highlights from the MASCC annual symposium.
Management of Febrile Neutropenia
Advances over the past few decades have led to reduced morbidity and mortality from chemotherapy-induced febrile neutropenia (FN). FN was once considered fatal, but in the modern era, mortality is about 5% and FN-related morbidity is about 20% to 30%. Complications can include hypotension, respiratory failure, intensive care unit admission, and confusion.
The MASCC scoring system for FN and the use of granulocyte colonystimulating factor (G-CSF) for prevention of FN in high-risk patients are the most important advances over the past 2 or 3 decades, explained Jean Klastersky, MD, Institut Jules Bordet, Université Libre de Bruxelles, Belgium.
“Mortality and morbidity are greatly reduced, and therapies are simpler, less toxic, and appropriately delineated according to patients’ risk status,” Klastersky told the audience. “Despite this progress, numerous challenges remain in patients at high risk, and further study is needed to define the optimal use of G-CSF.”
“Even a 5% mortality rate is too high,” he continued. “Some of the patients who die are young and treated with curative therapy.”
Treating an episode of FN is expensive, with much of the direct treatment costs driven by G-CSF. The mean cost of treating 1 episode of FN is $7700 for outpatients, and $15,231 for inpatients. “The cost is reduced by 50% if you can treat on an outpatient basis,” he said.
The MASCC scoring index, developed in 2000, enables risk stratification of patients who develop FN. A score >21 predicts a low risk of complications (ie, <5%). These patients can be treated with oral antibiotics as outpatients. Prerequisites for oral antibiotic therapy include: (1) low risk on MASCC scoring index, (2) feasibility of oral antibiotics, and (3) 24-hour hospitalization period for observation.
The rates of mortality and complications are higher in patients with a MASCC index score <15 versus >21. Mortality from gram-negative bacteremia is 43% in patients with a MASCC score <15, Klastersky noted.
“A low MASCC score predicts for severe sepsis. We need protocolized approaches for patients with FN and poor MASCC score. Some of these patients are kept too long in the emergency department—for several hours— without antibiotics. We should be more aggressive in selecting patients at high risk,” he continued.
The possibility of preventing FN with G-CSF has moved the field forward. Prophylactic use of G-CSF can decrease the incidence by about 50% and reduce mortality as well. The management algorithm for G-CSF is based on economic considerations, Klastersky noted, and now it is given when the risk of FN is >20%.
“I take issue with the fact that if the risk is >10%, G-CSF is not advised. This is not based on clinical science.”
Low-risk patients who develop FN have similar rates of complications and mortality as high-risk patients, and studies show that low-risk patients derive a similar benefit from G-CSF. Klastersky suggested expanding criteria for use of G-CSF as primary prophylaxis and exploring the possibility of shorter schedules for this expensive therapy.
Scrambler Therapy for Chemotherapy-Induced Peripheral Neuropathy
Current treatments for chemotherapy- induced peripheral neuropathy (CIPN) are suboptimal, according to Charles Loprinzi, MD, Mayo Clinic, Rochester, Minnesota. Drugs such as duloxetine, venlafaxine, and gabapentin are sometimes used off label and are not universally effective.
A recent study presented at the 2012 Annual Meeting of the American Society of Clinical Oncology showed that duloxetine reduced pain associated with CIPN by 30% in about onethird of patients. Although this reduction was clinically meaningful according to the authors, about twothirds of patients did not get better. Venlafaxine and gabapentin are used off label based on anecdotal evidence.
Loprinzi said that scrambler therapy “may offer a glimmer of hope” in this setting. A previous pilot study found that scrambler therapy reduced pain scores by 59% in 52 patients with neuropathic pain (Smith TJ, et al. J Pain Symptom Manage. 2010;40(6):883-891).
“At first I was skeptical about using scrambler therapy for CIPN, but I am encouraged by results of a pilot study at our institution,” he told listeners.
Scrambler therapy uses a device to treat pain via noninvasive cutaneous electrostimulation, substituting “pain” messages with “nonpain” messages; the device generates 16 different current patterns to stimulate nerve action potentials.
At MASCC, Deirdre R. Pachman, MD, Mayo Clinic, reported experience with scrambler therapy in the first 11 patients with CIPN-related pain: 8 were women, and 3 were men; mean age was 57 years; patients had been exposed to various chemotherapy regimens; and the majority of patients had symptoms for more than 2 years.
After 10 days of treatment, scrambler therapy decreased the average daily CIPN score (measuring pain, numbness, and tingling) as well as the worst daily CIPN score for these symptoms. Numbness was decreased by about 30% over 10 days, and pain and tingling were reduced by about 40%.
Loprinzi and colleagues plan to conduct a prospective, placebo-controlled trial to confirm these findings.
Control of Grade 1 Diarrhea Important
In the molecularly targeted therapy era, severe diarrhea continues to be a problematic side effect and accounts for increased resource utilization if not controlled.
“If grade 1 diarrhea is not appropriately treated, diarrhea can quickly spiral down to grades 2, 3, and 4 and risk of hospitalization and death,” Lowell Anthony, MD, Louisiana State University School of Medicine, New Orleans, told supportive care experts at MASCC. “Only you can really prevent the spiral of diarrhea.”
Conventional chemotherapy agents, such as fluorouracil (5-FU), irinotecan, paclitaxel, and epirubicin, cause diarrhea. With good supportive care, these drugs can be used in clinical practice.
“Even giving 5-FU via different routes is still associated with 10% to 20% severe diarrhea. An incidence of >20% is not acceptable,” he said.
Targeted agents, including bevacizumab, epidermal growth factor receptor inhibitors, sunitinib, and sorafenib, have an additive risk of diarrhea when combined with chemotherapy. “The only good news is that the rate of grades 3 and 4 diarrhea [with these agents] is under 10%, but they increase the rates of grades 1 and 2 diarrhea,” Anthony stated. “In general we don’t stop treatment with targeted therapy for grades 1 and 2 diarrhea. These rates are much lower than what we see with irinotecan.”
Bortezomib causes diarrhea (all grades) in about 45% of patients. Lapatinib causes grades 1 to 3 diarrhea in up to 64% of patients. Vandetanib causes grades 1 to 4 diarrhea in 56% of patients with thyroid cancer. Cabozantinib, used to treat solid tumors, causes grades 1 to 4 diarrhea in 57% of patients. Regorafenib, an investigational oral multikinase inhibitor, caused grades 1 to 4 diarrhea in 32% of patients with colorectal cancer, but more data are needed to establish risk.
“We are dealing with diarrhea in the context of other side effects caused by small molecule inhibitors; for example, peripheral neuropathy with bortez - omib; QTc prolongation with dasatinib; rash, diarrhea, fatigue, conjunctivitis with erlotinib; rash, loss of appetite, interstitial lung disease with gefitinib; rash, weight gain, edema with imatinib; hypertension, heart failure syndrome with sorafenib and sunitinib,” Anthony explained.
In clinical practice, diarrhea and its sequelae involve increased resource utilization, he continued. It is important to establish the diagnosis and etiology of diarrhea in cancer patients. Factors to consider in assessing risk of diarrhea include prior chemotherapy and prior pelvic radiation, performance status, response to prior cycle of chemotherapy, increased age, and female gender.
Guidelines suggest 3 drugs: loperamide, opium derivatives, and octreotide. Grades 1 and 2 uncomplicated diarrhea should be managed with adequate fluids, and the BRAT (bananas, rice, applesauce, and toast) diet. Grades 3 and 4 diarrhea may require hospitalization, antibiotics, octreotide, and fluids.
With tyrosine kinase inhibitor (TKI)-induced diarrhea, dosing adjustment is not usually needed for grades 1 and 2 diarrhea; dose reduction and intravenous fluids should be used to treat grades 3 and 4.
“We will never see a clinical trial of treating TKI-induced diarrhea. Treatment will be based on expert opinion,” Anthony said.
Studies are now evaluating probiotics and aluminum silicates for treatment of diarrhea. In Europe, glucagon-like peptide-2 is being studied in this setting, but these drugs cannot be used for chronic diarrhea, Anthony reported.